1. Field of the Invention
The present invention relates generally to the fields of biomedical engineering, biochemistry and medical treatment and surgical procedures. More specifically, the present invention provides methods, devices and compositions for inducing changes in biomolecules and bioactive molecules useful for accelerating or enabling certain reactions, fixing or fusing tissues and implants, dressing, sealing or closing a wound to reduce the loss of internal fluids, for enhancing wound healing and for delivery of active agents to tissues.
2. Description of the Related Art
Effective closure of surgical wounds, including incisions, tears and leaks in the patient's organs is critical to the success of the surgical procedure. This success is based on restoration of the physical integrity and function of injured or diseased tissue. Failure to close surgical wounds optimally can also result in serious and excessive scarring. A variety of devices have been developed to assist the surgeon with surgical closure of tissue, including sutures, staples and fibrin glues.
Historically, wound dressings consist of some type of bandage or adhesive. More recently, wound sealing methods whereby energy is directed to the tissue have been tested and occasionally are used clinically. Traditional techniques of managing the wound include cleansing and debriding, treating with antibiotics and applying a dressing. Modern wound care products often seek to provide moisture, pH balance and nutrition in an effort to improve the potential for healing. The healing process may also complicate the status of the patient through formation of scar tissue. This scarring helps to close the wound, but its formation is accompanied by contraction and buildup of tissue which can lead to a loss in flexibility at the wound site and, in severe cases, may result in loss of mobility to the patient.
Conventional methods of wound closure following surgery consist of applying sutures or staples to join two or more tissues that have been dissected. While these methods are generally successful, at times complications arise due to inadequate closure of the wound that could result in the tissues separating or in “leakiness.” In particular, the quality of suturing depends on manual dexterity of the surgeon and adequate access to the wound. Current designs of surgical clips can slip if applied incorrectly or accidentally disturbed. Surgical clips can also cause damage to the vessels or structures to which they are applied if the surgeon applies excessive compression force. With the increasing use of minimally invasive surgical methods, such as endoscopy, wound access and the efficient closure of wounds has become a significant issue in medicine.
A surgeon's skill is less of a factor where surgical staples are employed and, as a result, less invasive devices have been developed for effective delivery of staples through endoscopic trocars. This has led to greater acceptance for stapling devices over suturing during less invasive surgical procedures. Nonetheless, conventional stapling is limited in that it usually requires an anvil be placed behind the tissues to be joined, and that enough space is available to produce the necessary force to form the staple against the anvil.
Various methods have been employed to fasten tissues together without the use of a conventional staple or suture. These devices often employ springs or another compression mechanism to pull the tissues together. Shape memory alloys have been employed in U.S. Pat. Nos. 4,485,816 , 5,002,562 and 6,113,611 and, in at least one case, using electronic heating of the fastener to make it close. U.S. Pat. No. 5,725,522 discloses the employment of lasers to effect suture “fusion” whereby two ends of the suture are fused together in place of the traditional knot.
A trend toward the use of minimally invasive surgical techniques has created a demand for wound closure methodology that can be used through a small incision in the patient. Sutures cannot easily be secured by traditional methods through an endoscope and current stapling methods generally require an anvil be placed behind the tissue thereby limiting their use. U.S. Pat. No. 6,358,271 describes the use of sutures composed of a fused loop of filamentous material which is ultrasonically welded. This application has the advantage of a low profile of suture closure as compared to the traditional knot and may ultimately be applied endoscopically, however the technology still requires the use of a fairly large securing device including an anvil. U.S. Pat. Nos. 6,409,743 and 6,423,088 discuss c-shaped collars that are made out of a material that fuses to itself upon the application of energy in the form of heat, light, radiofrequency waves, electricity or ultrasound.
More recently, wound sealing approaches, which employ methods of directing energy to the tissue which as a consequence adheres to proximal tissue, have been tested and used clinically. Commercial electrosurgery and electrocautery devices commonly are used for sealing internal wounds, such as those arising through surgical intervention. Inventions for sealing vessels using other forms of electromagnetic energy have been published. U.S. Pat. No. 6,033,401 describes a device to deliver adhesive and apply microwave energy to effect sealing of a vessel. U.S. Pat. No. 6,179,834 discloses a vascular sealing device to provide a clamping force, while radiofrequency energy is applied, until a particular temperature or impedance is reached. U.S. Pat. No. 6,132,429 describes using a radiofrequency device to weld blood vessels closed and monitoring the process by changes in tissue temperature or impedance. Nevertheless, these devices are generally unsuitable for the purpose of occluding a wound thereby enhancing long-term healing.
Over the past fifteen years, a significant amount of scientific research has focused on using laser heated “solder” for “welding” tissues such as blood vessels (1-2). Research has been done on laser tissue welding with albumin solders which are an improvement over conventional suture closure because it offers an immediate watertight tissue closure, decreased operative time, especially in microsurgical or laparoscopic applications, reduced trauma, and elimination of foreign body reaction to sutures, collagen-based plugs and clips. The procedure has been enhanced with the use of advanced solders, strengthening structures, concurrent cooling, and added growth factors as disclosed, for example, in U.S. Pat. No. 6,221,068.
Use of lasers for tissue welding appeared very promising, however, over the years the techniques have been shown to present certain limitations. The laser energy must be manually directed by the surgeon which leads to operator variability. Additionally, the radiant energy is not dispersed evenly throughout the tissue. The high energy at the focal point may result in local burns and the heating effect drops off rapidly at a small distance from the focal point. Finally, lasers are expensive and currently cannot be miniaturized easily.
A number of patents describe using electromagnetic energy, often in the form of laser or other radiant energy, to heat tissue or a biocompatible “solder” to effect tissue sealing or fusion. U.S. Patent Publication Nos. 2003/019862 and 2003/0195499, for example, describe microwave antennae suitable for cutting or ablating tissue. U.S. Pat. No. 5,925,078 describes using a form of energy, such as microwaves or radiofrequency, to fuse endogenous collagen fibrils in tissue, whereupon the strength of the fusion is enhanced by subsequent chemically-induced protein cross-linking. U.S. Pat. No. 6,669,694 uses a different application of energy, in the form of a vaporized biocompatible material, which exits an applicator to impinge on tissue in order to effect a beneficial tissue effect. Neither Anderson nor Shadduck describe using an additional adhesive during the described processes.
Menovsky and co-workers (Effect of CO2-milliwatt laser on peripheral nerves: Part II. A histological and functional study, Microsurgery 20, pp 150-155, 2000) showed that by using an albumin solder applied to a sciatic nerve and cured with the radiant energy produced by a CO2 laser, it was possible to elicit nerve repair without causing unacceptable thermal side-effects. Lauto et al. (Laser-activated solid protein bands for peripheral nerve repair: an vivo study. Lasers in Surgery & Medicine. 21, pp 134-41, 1997) and McNally-Heintzelman et al. (Scaffold-enhanced albumin and n-butyl-cyanoacrylate adhesives for tissue repair: ex vivo evaluation in a porcine model. Biomedical Sciences Instrumentation. 39, pp 312-7, 2003) found beneficial results of laser-nerve welding using other laser radiant energy and differing adhesive compositions. Nevertheless, the lack of control and the inability to induce uniform heating in the nerve as a result of laser irradiation restricts the utility of laser-nerve welding to the laboratory. Becasue of this, the procedure is not used in the clinic on human patients.
There has been an effort recently to identify biocompatible molecules which can be used as a “tissue solder”. Biomolecules such as fibrin, elastin, and albumin have been or are used to “glue” tissue to tissue. A number of patents describe the “activation” of these biomolecules to form “welds” through irradiation, often in the form of laser radiant energy, but sometimes in the form of ultrasound or radiofrequency waves. The applied energy is believed to denature the molecules, which then adhere to one another or cross-link to one-another and to protein in tissues, thereby effecting a union between the tissues.
Over the past fifteen years, a significant amount of scientific research has focused on using laser heated “solder” for “welding” tissues such as blood vessels (1-2). Research has been done on laser tissue welding with albumin solders which is an improvement over conventional suture closure because it offers an immediate watertight tissue closure, decreased operative time, especially in microsurgical or laparoscopic applications, reduced trauma, and elimination of foreign body reaction to sutures, collagen-based plugs and clips. The procedure has been enhanced with the use of advanced solders, strengthening structures, concurrent cooling, and added growth factors, e.g., as disclosed in U.S. Pat. Ser. No. 6,221,068.
Use of lasers for tissue welding appeared very promising, however, the techniques have certain limitations. The laser energy must be manually directed by the surgeon, which leads to operator variability. Additionally, the radiant energy is not dispersed evenly through the tissue. The high energy at the focal point may result in local burns and the heating effect drops off rapidly at a small distance from the focal point. Finally, lasers are expensive and currently cannot be easily miniaturized.
U.S. Pat. No. 5,669,934 describes a method for joining or restructuring tissue consisting of providing a preformed film or sheet of a collagen and/or gelatin material which fuses to tissue upon the application of continuous inert gas beam radiofrequency energy. Similarly, U.S. Pat. No. 5,569,239 describes laying down a layer of energy reactive adhesive material along the incision and closing the incision by applying energy, either optical or radiofrequency energy, to the adhesive and surrounding tissue. Furthermore, U.S. Pat. Nos. 5,209,776 and 5,292,362 describe a tissue adhesive that is principally intended to be used in conjunction with laser radiant energy to weld severed tissues and/or prosthetic material together.
U.S. Pat. No. 6,110,212 describes the use of elastin and elastin-based materials which are biocompatible and can be used to effect anastomoses and tissue structure sealing upon the application of laser radiant energy. The stated benefits, inter alia, are the biocompatible and ubiquitous nature of elastin. U.S. patent application Ser. No. 20020198517 discloses the use of laser tissue-welding employing an adhesive consisting mostly of gelatin which effects tissue attachment.
Furthermore, U.S. Pat. No. 6,302,898 describes a device to deliver a sealant and energy to effect tissue closure. The tissue is pre-treated with energy in order to make the subsequently applied sealant adhere better. In International Publication WO 99/65536 pre-treatment of a substantially solid biomolecular solder prior to tissue repair use is taught.
U.S. Pat. No. 5,713,891 describes the addition of bioactive compounds to the tissue solder in order to enhance the weld strength or to reduce post-procedure hemorrhage. U.S. Pat. No. 6,221,068 discloses the importance of minimizing thermal damage to the tissue to be welded. By using pulsed laser radiation and allowing the tissue to cool to nearly the initial temperature between each heating cycle, the damage is minimized.
U.S. Pat. No. 6,323,037 describes the addition of an “energy converter” to the solder mixture such that incident optical energy will be efficiently and preferentially absorbed by the solder which subsequently effects a tissue weld. Similarly U.S. Pat. No. 6,348,679 describes using a radiofrequency “susceptor”, i.e., a compound that absorbs RF energy and converts it to heat.
U.S. Pat. No. 5,749,895 describes using a tissue adhesive which is heated in proximity to a mechanical support with radiofrequency heated inert gas. U.S. Pat. No. 6,547,794 describes using a bony material implant, to which a tissue adhesive is applied, inserted between the surfaces of bones to be fused, and to which energy is applied to achieve the weld. U.S. Pat. No. 5,749,895 and U.S. Pat. publication No. 2003/019866 disclose a device and method for sealing tissue punctures with a fluent closure composition precursor heated with the energy emitted from a microwave antenna. None of these aforementioned inventions describe the use of a material within the adhesive which serves to enhance the absorption of the incident energy relative to the surrounding tissue. Materials to enhance the absorption of optical radiation during tissue welding have been described in numerous patents and patent applications, e.g. U.S. Patent Publication 2002/0198517; these inventions generally focus on optical means of tissue sealing and welding. The prior art fails to describe adequate means for delivering compositions that may be activated using radiofrequency energy sources.
Common problems exist throughout the prior art. These include, for example, tissue damage due to uneven heating, unknown and/or uncontrollable thermal history, i.e., time-temperature profile, and relatively high cost. It is notable that a consistent means of treatment and control are desirable. The Code of Federal Regulations, 21 CFR 860.7(e)(1), establishes that there is “reasonable assurance that a device is effective when it can be determined, based upon valid scientific evidence, that in a significant portion of the target population, the use of the device will provide clinically significant results.” Devices that cannot be shown to provide consistent results between patients, or even within a patient upon multiple use, will have minimal utility and may not be approvable for broad use. Beyond devices, it is generally desirable to develop medical products with critical controls that can deliver precise results.
Inductive heating (3) is a non-contact process whereby electrical currents are induced in electrically conductive materials (susceptors) by a time-varying magnetic field. Generally, induction heating is an industrial process often used to weld, harden or braze metal-containing parts in manufacturing where control over the heating process and minimized contact with the workpiece are critical. Basically, radiofrequency power is coupled to a conducting element, such as a coil of wire, which serves to set up a magnetic field of a particular magnitude and spatial extent. As a result, induced currents or Eddy currents flow in the conductive materials in a layer referred to as the skin depth δ, given by:δ=√(2ρ/μω)where ω is frequency (rads/s), ρ is resistivity (ohm-m) and μ is the permeability (Webers/amp/m) which is the product of μo the permeability of free space and μr the relative permeability of the material.
The magnetic permeability of a material is quantification of the degree to which it can concentrate magnetic field lines. Note, however, that the permeability is not constant in ferromagnetic substances like iron, but depends on the magnetic flux and temperature. The skin depth at room temperature at 1 MHz electromagnetic radiation in copper is 0.066 mm and in 99.9% iron is 0.016 mm.
The consequence of current flowing is Joule heating. The skin-depth formula leads to the conclusion that, with increased frequency, the skin depth becomes smaller. Thus, higher frequencies favor efficient and uniform heating of smaller components.
In certain situations, localized heat can also be generated through hysteresis losses or frictional heating as the susceptor moves against physical resistance in the surrounding material. Consideration of Joule heating alone results in a formula for the power-density P(W/cm3) in the inductively-heated material:P=4πH2μoμrfM where H is the root means square (RMS) magnetic field intensity (A/m), f is frequency (Hz), M is a power density transmission factor (unitless) which depends on the physical shape of the heated material and skin depth and diameter of the part to be heated (4-5).
M, which is equal to the product of F and d/δ, where F is a transmission factor and d is the diameter of the part, can be shown to be maximally about 0.2 when the object diameter is 3.5 times the skin depth, and when certain other assumptions are made. Thus, for a given frequency, there is a diameter for which the power density is a maximum or, equivalently, there is a maximum frequency for heating a part of a certain diameter below which heating efficiency drops dramatically and above which little or no improvement of heating efficiency occurs. It also can be shown that the power density of inductively heated spheres is much higher than solid spheres of the same material.
There are only a few examples of the use of inductive heating in the medical literature. The oldest example of use of therapeutic inductive heating is in hyperthermia of cancer, whereby large metallic “seeds” are inductively heated using a coil external to the body (6). Smaller seeds were used where small biocompatible dextran magnetite particles in magnetic fluid was used to treat mouse mammary carcinoma by hyperthermia (7). U.S. patent application Ser. No. 2002/0183829 describes inductively heating stents made of alloys with a high magnetic permeability and low curie temperature for the purpose of destroying smooth muscle cells in restenosing blood vessels. A more recent report described the diagnostic use of induction heating to heat nanocrystals coupled to DNA in order to locally denature DNA for the purpose of hydridization (8).
The literature is deficient in descriptions whereby biomolecules are heated through induction. U.S. Pat. No. 6,348,679 discloses compositions used in bonding two or more conventional materials where the interposed composition consists of a carrier and a susceptor, which may be at least in part composed of certain proteins. However the applications apply to conventional substrates such as films or wood. The effects of induction in tissue are not limited to tissue fusion. U.S. Pat. No. 6,573,491 and International Publications WO 00/69515 and WO 00/77045 describe specific formulations, methods and devices where electromagnetic energy absorption is maximized relative to the surrounding medium, resulting in effects such as accelerated reaction rates and molecular mobility. One method of accomplishing this energy absorption is through inductive heating.
Many surgeries would benefit from the use of sutureless wound closure methods and improved methods of sealing tissues. Surgery of the colon or rectum is often performed in patients with colorectal cancer and inflammatory bowel disease. The surgery involves removal of the diseased tissue and an anastomosis of the juxtaposed ends. In 2000, approximately 162,000 intestinal anastomoses were performed in the U.S. While advances in surgical techniques have improved outcomes, one of the most severe and life-threatening complications is anastomotic leakage, which occurs in 0-20% of cases, with a mortality rate ranging between 6 and 22%. The cost of colorectal cancer in the U.S. was estimated at $5.4 B in 2000. Small anastomotic leaks can be treated with percutaneous drainage, antibiotics, bowel rest and total parenteral nutrition to promote spontaneous closure. A large, free leak requires prompt laparotomy with stoma creation. Treatment protocols for these complications increase morbidity, mortality, hospital time and expense. Clearly a way to improve colonic anastomoses could have a profound positive effect on patient care and the health-care financial burden.
Tens of millions of venous access and puncture wounds are created each year as a result of catheterization procedures, biopsies, hemodialysis treatments and other procedures. Manual compression has been the standard of care for closure after percutaneous coronary interventions, but it requires prolonged bed rest, e.g. 4-12 hours, leading to delayed ambulation, significant medical staff time and associated higher costs. The routine administration of anticoagulant medication to prevent blood clots and stroke during the diagnostic or interventional procedure can further delay sealing the vessel and postpone ambulation. Complication rates as high as 12.5% for extraction atherectomy, and 11% for balloon angioplasty have been reported.
In recent years, several closure devices have been introduced to the market. Suture-mediated closure (SMC) devices push a shaft into the artery and use stitches to suture and close the puncture. When compared to manual compressison, the advantages of SMCs are a quicker time to hemostasis, 5 minutes vs. 25 minutes, and ambulation, 1 hour vs. 4-6 hours. However, these devices generally require a trained physician to insert the sutures, while most other closure devices can be managed by non-physicians. Reported complications include an increase in the number of access site infections, as well as pain and discomfort for the patient.
Some collagen-based closure devices use a biodegradable bovine collagen plug to form a coagulum at the access site. The two primary types are a plug, e.g. VasoSeal™ and a collagen plug with an anchor, such as Angio-Seal™. Hemostasis success rates range from 88%-100%, with an average success of 97%. When compared to manual compression, most studies show results similar to those for SMCs, i.e., a decrease in time to ambulation, 1 hour vs. 4-6 hours and time to hemostasis, 5 minutes vs. 25 minutes, and, furthermore, a 1 day reduction in hospital stay. Data on complications is mixed, with several studies showing minor complications comparable to compression, but an increase in major complications that require surgical repair. Other studies show an increase in minor complications. Collagen-based devices seal the vessel, but fail to seal the tract. In addition, manufacturers recommend that healthcare professionals not use the sealed vessel for a period of 3-6 weeks while the collagen plug is absorbed.
Manual pressure is the current standard of care for stopping post-dialysis bleeding as well. Limitations to manual pressure include: (1) the 10 to 20 minutes it typically takes to stop bleeding, occasionally taking up to an hour for difficult cases; (2) patients routinely receiving anticoagulant agents during their treatment thus lengthening the time required to stop the bleeding and leave the clinic; (3) applying too little pressure doesn't stop the bleeding, resulting in excess blood loss; (4) applying too much pressure causing the access to thrombose which requires additional interventions; and (5) manual pressure is labor intensive for the dialysis staff when patients are unable to hold their own site following needle removal. Success in rapidly and completely stopping the bleeding and sealing the tissue following the treatment can reduce complications such as infection and post-dialysis bleeding, as well as preserving the access.
Of the hundreds of thousands of Americans living with end stage renal disease, more than half undergo hemodialysis treatments 2-3 times each week. One challenge associated with successful hemodialysis is vascular access, the method used to access a patient's blood supply. Complications related to vascular access include thrombosis, stenosis, infection, pseudoanuerysm, limb ischemia and post-dialysis bleeding. The complications lead to loss of vascular access and the need for corrective surgery in the vast majority of patients twice per year. These corrective surgeries normally involve replacing an arteriovenous fistula or synthetic graft which provides access to the patient's blood supply.
The inventors recognize a need in the art for a precision device and improved methods of joining tissues which have been separated through surgery or through trauma, particularly during minimally invasive procedures. The prior art is particularly deficient in devices and methods for minimally-invasive methods that use electromagnetic energy to controllably alter a biocompatible structure thereby making it adhere to tissue through molecular alterations and/or mechanical shrinkage. The present invention fulfills this longstanding need and desire in the art.